In recent years, much research has been done in developing systems using polymeric compositions with a programed release of active agents, especially drugs, over periods of times. The purpose of these systems is to dispense the agent at a controlled and, if desired, constant rate in order, as in the case of pharmaceutical agents or drugs, to improve therapy by presenting the drug in a most beneficial and reliable manner, with a minimum possibility of complications from the drug or from failure to comply with the therapeutic regime.
Although controlled release of drugs can be accomplished by several mechanisms, biodegradation of an insoluble polymer carrier to soluble monomer units offers the advantage of eliminating the need for surgical removal of the device. However, the development of controlled release systems using bio-erodible polymers has not advanced as quickly as the non-erodible systems and at present, no bio-erodible system has been approved by the Food and Drug Administration for clinical application. In addition, there have been very few bio-erodible polymers developed for biomedical use, and unfortunately very few of the polymers were designed initially with the intention of releasing drugs in a controlled manner. This design deficiency has caused difficulty in developing effective controlled release dosage forms from these polymers.
The ideal situation for an effective bio-erodible system is one where the drug is uniformly distributed through the polymer and where surface erosion is the only factor permitting drug release to occur in order to obtain advantageous cost and dosage form design. With an erosion rate constant, k, the rate of release dM/dt is equal to the product of k and the surface area of the system. Therefore, to obtain zero-order release, it would be necessary to utilize a geometry that does not change its surface area as a function of time. Such ideal systems would also possess the following additional advantages: (1) simple release mechanism which is independent of drug properties, (2) ability to linearally vary drug delivery rate by linerally varying the load of the device with a drug, (3) conservation of mechanical integrity since erosion occurs only at the surface of the device, (4) linearally vary device life by linearally varying device thickness and (5) elimination of the polymer and drug concomitantly.
However, the ideal situation described in which surface erosion is the only factor responsible for drug release and with the polymer degraded to small nontoxic products, has never been found in practical usage and this makes it difficult to achieve zero-order release and difficult to control release kinetics. Worse still, bulk erosion often occurs in addition to surface erosion rendering the system sponge-like which causes even greater difficulty in both controlling release because of multiple phenomena (including diffusion), taking place and accomplishing zero-order release.
The reason for the bulk erosion problem is that almost every bio-erodible polymer which has been developed for biomedical use such as polylactic acid has been hydrophilic and imbibes water into the center of the matrix. It is not surprising since most bio-erodible polymers developed for biomedical use where designed for use as suture materials rather than for controlled release application. In addition to polylactic acid, other hydrophilic polymers have been studied including polyglutamic acid, polycaprolactone and lactic/glycolic acid copolymers. However, while these systems may be useful under certain circumstances, they still possess the above-mentioned limitations.
The only bio-erodible hydrophobic polymer which has been designed for drug delivery systems are polyorthoesters. They have advantages in that they are not only hydrophobic, but their hydrophobicity is pH-sensitive and this has proven useful in regulating drug release. However, although different types of polyorthoesters have been synthesized, they have been reported to possess certain disadvantages such as (1) by themselves, they are often too hydrolytically stable for controlled drug release, e.g. 7% by weight erodes in over 220 days. They therefore need the inclusion of acid catalysts to promote bio-erosion. (2) They also swell a great deal as a result of the incorporation of sodium carbonate into the matrix, the rate of swelling often contributes more to determining release rates than does the rate of erosion. Also, the degradation products are not as simple as some other bio-erodible polymers such as polylactic acid which has the advantage that the ultimate degradation products are water and carbon dioxide.
It would be highly desirable to provide a hydrophobic bio-erodible polymer system for controlling drug release wherein the erosion intermediates and products are nontoxic and are readily eliminated or metabolized by the body. In addition, it would be desirable to provide such a polymer system which does not cause adverse tissue reaction. In addition, it would be desirable to provide such a system that exhibits mechanical and physical integrity, is unswellable, is tight enough to prevent diffusion, is easy to synthesize and form and is stable on storage.